Patients with head and neck cancer (SCCHN) often develop resistance to treatment, which leads to tumor recurrence. Consequently, almost half of SCCHN patients die within five years of diagnosis. Cancer-initiating cells (CIC) survive successful treatment to regenerate a tumor (recurrence) and spread to distant sites. SCCHN is a neurotropic cancer i.e. it invades nerves, which is an important route of tumor spread. In normal tissues, the nerves have an essential role in tissue regeneration. Surprisingly, the impact of nerves on tumor recurrence and tumor spread via effects on CIC has not been investigated. In pilot studies, we show that nerves have an important role in tumor progression. Furthermore, a neuropeptide released by nerves induces transcription of multiple pro-invasive cytokines in SCCHN by activating a transcription factor. The strategic objective of this proposal is to investigate the impact of nerves on tumor progression via survival and spread of CIC. The hypothesis is that peripheral nerves promote tumor recurrence and spread via cytokines that promote survival, invasion, and proliferation of CIC. The rationale is that investigation of the neural niche for CIC will elucidate an overlooked mechanism of CIC survival and tumor recurrence thereby revealing an important treatment target. We will test the hypothesis by pursuing the following aims: 1) To investigate the impact of nerves on CIC-mediated tumor recurrence and metastasis; and 2) To investigate the mechanism of nerve- induced tumor progression. Thus, the proposed studies will investigate an important but understudied area of CIC-mediated tumor regeneration and metastasis.